Aromatic core amino acids

A prior distribution for sequence profiles can be derived from mixtures of Dirichlet distributions [16,51-54]. The idea is simple Each position in a multiple alignment represents one of a limited number of possible distributions that reflect the important physical forces that determine protein structure and function. In certain core positions, we expect to get a distribution restricted to Val, He, Met, and Leu. Other core positions may include these amino acids plus the large hydrophobic aromatic amino acids Phe and Trp. There will also be positions that are completely conserved, including catalytic residues (often Lys, GIu, Asp, Arg, Ser, and other polar amino acids) and Gly and Pro residues that are important in achieving certain backbone conformations in coil regions. Cys residues that form disulfide bonds or coordinate metal ions are also usually well conserved. 

Helical heptad repeat sequences have been reported to be well behaved although they are difficult to characterize by NMR spectroscopy due to spectral overlap. The motifs that have been shown to have native-like properties, and are not highly repetitive, have cores composed of aromatic amino acid side chains of, for example, phenylalanine and tryptophan. In four-helix bundle motifs [1, 2], the /1/la-motif BBAl [5] and the /1-sheet protein Betanova [9], the formation of the folded structure appears to be strongly dependent on such residues although the energetics have not been calculated by substitution studies. As a tentative rule, therefore, the probability of success in the design of a new protein is probably much higher if residues are included that can form aromatic clusters in the core (Fig. 5). 

It should also be kept in mind that the Beer-Lambert law often is not vahd at higher concentrations, since there occur interactions between chromophores and other molecules . This effect is observed especially at reading of proteins in the UV. The solvent may influence the absorbance too, because, for example, some of the aromatic amino acid residues are buried within hydrophobic core of the molecule and become exposed during unfolding of the protein when the composition of the solvent is changed or the protein is denaturated by dilution. 

While cyclic peptides have proven to be problematic, we beheve that amino acids are ideal candidates for derivatization of our macrocyclic scaffolds. Mary natural and unnatural amino acids with appropriately protected side chains are commercially available or can be readily prepared providing facile access.22 The a-amino- and a-carboxy- groups common to all of these will provide constant sites for attachment to a macrocyclic scaffold core. Side chains varying in aromatic, aliphatic, polar and ionic characters should provide sufficient chemical diversity. Finally, amino acids may be combined in many ways to form short acyclic peptides, allowing access to more diverse chemical properties not found in individual amino acids. 

As a first step toward this purpose, we have studied the chelation effect of tetrapeptides of sequences Cys-X-Y-Cys, by preparation of metal complexes of mainly the first transition series. The hydrophobic effect of the peptides was also studied by utilizing the side chain bulkiness of the amino acid residues interposed between the two cysteine residues. A special effect of aromatic side chains of tyrosine, phenylalanine, and tryptophan has also been examined in order to assess their ability to ease electron transfer to and from the nearby iron core. 

The amino acids with nonpolar, aliphatic side chains, Ala, lie. Leu, Met, and Val, are sufficiently hydro-phobic that they are most often buried in the generally hydrophobic core of non-membrane-embedded proteins. Note that lie and Val have particularly sterically hindered P-carbons. Of the aromatic amino acids. His, with a pK of around 6, will mostly be in the uncharged form at physiological pH values (therefore more often hydrophobic than polar), and will be a likely choice for reactions which involve proton transfer. Phe and Trp are clearly hydrophobic. Despite having a polar hydroxyl group, if we consider the free energy required to transfer... 

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